This invention relates to pharmaceutical compositions which are useful in effecting transdermal delivery of a therapeutic dose of a therapeutically active ingredient to the systemic circulation of a mammal.
As a specific and preferred application, therapeutically active ingredients or drugs such as opioids may be singled out as preferred active ingredients in such transdermal systems.
Many opioids are known to have poor bioavailability in the mammalian systemic circulation due to extensive initial metabolism of the drug by the liver and intestines. Furthermore, the bioavailability of orally administered opioids may be unpredictable since various factors such as changes in acidity and food content can cause changes in the amount of drug absorbed from the gastrointestinal tract. Also, oral administration does not necessarily insure good patient compliance.
Parenteral administration of opioids provides better bioavailability than oral administration. However, the various routes of parenteral administration such as intravenous, intramuscular, and subcutaneous delivery are not convenient for chronic therapy. This is particularly true for those opioids which exhibit short biological activity half-lives.
Topical formulations of opioids do not necessarily provide delivery of a therapeutic dose of the drug to the systemic circulation and thus provide poor or unpredictable bioavailability. Natural oils containing saturated or unsaturated fatty acids have been described in such topical formulations with drugs used for local anesthetic purposes.
Transdermal delivery of opioid drugs to the mammalian systemic circulation have been described as an alternative mode of administration which can provide the following advantages:
1. Improved and predictable bioavailability of the opioid as compared to oral administration since transdermal delivery avoids initial metabolism by the liver and intestines, and unpredictable absorption from the gastrointestinal tract.
2. A stable blood serum level of the drug resulting in a prolonged pharmacological effect similar to intravenous infusion.
3. Easily adjustable dosing rate which provides maximization of efficacy and minimization of side effects.
4. Easily removable drug source which provides rapid cessation of dosing and elimination of the drug from the body fluids.
5. Convenience of dosing which provides improved patient comfort as compared to parenteral administration and the possibility of greater patient compliance as compared to oral administration.
Transdermal drug delivery is distinguished from topical drug delivery by the fact that while a transdermal formulation is specifically designed to provide a predictable and therapeutically significant rate of delivery of the drug to the systemic circulation, a topical formulation is specifically designed to provide a therapeutic effect only to the local area to which the drug is applied. Furthermore, topical formulations are often designed to prevent any systemic delivery of the drug in order to minimize side-effects. However, even if the topical delivery of a drug does result in systemic absorption, the amount of drug delivery to the circulation is variable and uncontrolled.
European patent publication 0 171 742 describes such a system for the transdermal delivery of opioids using saturated or unsaturated fatty alcohols as acids or esters thereof with a carrier or vehicle such as propylene glycol resulting in an organic system, i.e. suspension or gel. The disadvantage of this system is that the use of propylene glycol or other known organic solvents causes irritation to the skin.
It has now been found that saturated or unsaturated fatty acids or esters thereof, such as linoleic acid, is effective as a skin absorption enhancer in purely aqueous systems thus leading to new and effective transdermal compositions without skin irritation.